Angiogenic and molecular diversity determine hepatic melanoma metastasis and response to anti-angiogenic treatment

Sebastian A Wohlfeil,Cyrill Géraud,Ana Olsavszky,Anna Lena Irkens,Kai Schledzewski,Anna Sophia Jauch,Céline Weller,Verena Häfele,Philipp-Sebastian Reiners-Koch,Sergij Goerdt,Christian David Schmid,Bianca Dietsch,Manuel Winkler,Carsten Sticht

doi:10.1186/s12967-022-03255-4

Abstract

BackgroundCutaneous melanoma exhibits heterogeneous metastatic patterns and prognosis. In this regard, liver metastasis, which is detected in ~ 10–20% of stage 4 patients, came to the fore of melanoma research, as it recently evolved as decisive indicator of treatment resistance to immune checkpoint inhibition.MethodsHepatic metastases were induced by intrasplenic injection of five different murine melanoma cell lines. The efficiencies of hepatic colonization, morphologic patterns, gene expression profiles and degree of vascularization were analyzed and Sorafenib was applied as anti-angiogenic treatment.ResultsWT31 melanoma showed the highest efficiency of hepatic colonization, while intermediate efficiencies were observed for B16F10 and RET, and low efficiencies for D4M and HCmel12. RNAseq-based gene expression profiles of high and intermediate metastatic melanomas in comparison to low metastatic melanomas indicated that this efficiency predominantly associates with gene clusters involved in cell migration and angiogenesis. Indeed, heterogeneous vascularization patterns were found in the five models. Although the degree of vascularization of WT31 and B16F10 metastases differed, both showed a strong response to Sorafenib with a successful abrogation of the vascularization.ConclusionOur data indicate that molecular heterogeneity of melanomas can be associated with phenotypic and prognostic features of hepatic metastasis paving the way for organ-specific anti-angiogenic therapeutic approaches.

Highlights

Cutaneous melanoma exhibits heterogeneous metastatic patterns and prognosis
Since Cutaneous melanoma (CM) differ in underlying driver mutations as well as their clinical and morphologic features, five murine melanoma cell lines with heterogenous driver mutations were selected (Table 1) to evaluate their ability to colonize the liver
WT31 melanoma reliably led to development of hepatic metastases and high numbers of metastatic nodules even at low cell concentrations

Summary

Introduction

Cutaneous melanoma exhibits heterogeneous metastatic patterns and prognosis In this regard, liver metastasis, which is detected in ~ 10–20% of stage 4 patients, came to the fore of melanoma research, as it recently evolved as decisive indicator of treatment resistance to immune checkpoint inhibition. In murine models of colorectal carcinoma (CRC) and melanoma, subcapsular injection of MC38 CRC or B16F10 melanoma cell lines into the liver abolished the response of corresponding subcutaneous tumors to ICI The authors tie this to infiltration of regulatory T-cells into the subcutaneous tumors which in turn recruit CD11b+ monocytes [6]. Most recently, these findings were extended by the fact that liver metastases of CRC and melanoma recruit tumor-specific CD8+ T-cells from the periphery, which underwent apoptosis, and, as consequence, induced systemic immunosuppression and reduced response to ICI [7]

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Discussion

Conclusion